MX2012006649A - Fty720 halogenated derivatives. - Google Patents

Abstract

There is provided new iodo- or bromo-compounds and their use as diagnostic agents and imaging agents for diseases or disorders where S1P receptor expression is altered. There is provided new iodo- or bromo-compounds and their use as diagnostic agents and imaging agents for diseases or disorders where S1P receptor expression is altered. The invention relates to a device for the autofrettage of workpieces (3), comprising a circumferentially closed housing (2) having an inner face (25) for receiving the workpiece (3), at least one sealing element (4) for closing an opening (5) of the workpiece (3), and a feed unit (12) for feeding an autofrettage medium into an inner space of the workpiece (3), wherein the sealing element (4) is arranged on the inner face (25) of the housing (2) and has a radially movable piston (6) for closing the opening (5).

Description

HALOGENATED DERIVATIVES OF FTY720 The present invention relates to novel compounds in particular to novel radioactive compounds, their preparation and the use of such radioactive compounds as radio-trackers / markers for imaging techniques and diagnostic tools in the field of diseases or disorders related to radioactive receptors. S 1 P, such as autoimmune diseases, neurodegenerative diseases, brain diseases or demyelinating diseases, for example, multiple sclerosis.

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults and the most common demyelinating disorder of the central nervous system. MS takes several forms and almost any neurological symptom can appear: the symptoms occur either in discrete attacks (recurrent forms) or that accumulate slowly over time (progressive forms). Between attacks, symptoms may disappear, but permanent neurological disorders often occur, especially as the disease progresses. As the signs and symptoms of MS can be similar to many other medical problems, this disease is difficult to diagnose. Diagnostic criteria have been established to facilitate and standardize the diagnostic process, including neuroimaging and magnetic resonance imaging (MRI) analysis of the brain and spine to visualize and follow the areas of demyelination (plaques or MS lesions). .

But currently there is no diagnostic test which is perfectly specific for MS, only biopsies or post-mortem tests can produce an absolutely safe diagnosis. Therefore, there is a strong medical need for an effective method to diagnose multiple sclerosis.

Nuclear mageology techniques, non-invasive, can be used to obtain information about the physiology and biochemistry of living subjects, including experimental animals, patients and volunteers. These techniques are based on the use of imaging instruments that can detect the radiation emitted from radio-trackers admistrated to live subjects. The obtained information can be reconstructed to provide flat and tomographic images, which reveal the distribution and / or concentration of the radio-tracker as a function of time. Examples of such techniques, which are particularly interesting for multiple sclerosis, brain diseases or demyelinating diseases, are Positron emission tomography (PET), a nuclear medicine imaging technique which produces a three-dimensional image or medical imaging tomography. nuclear, which produces a three-dimensional image or computed tomography of emission of simple photons (SPECT), a nuclear medicine tomographic imaging technique that uses gamma rays.

One of the requirements for the use of these techniques is the availability of an adequate tracker. Such a tracer can accumulate, for example, in specific organs or tissues; so its Visualization after administration allows visualizing these tissues or organs. Or it may have a characteristic activity (for example, it has a binding efficacy for specific receptors), which is distributed or modified in some way in case of a disease or disorder (for example, if such specific receptors are involved in these diseases or disorders); thus, its visualization in the body will allow detecting, staggering or following up such diseases or disorders. To visualize that compound is radiolabelled. Therefore, it is necessary that radiolabelling does not alter the specific properties of the compound.

Many diseases or disorders are known or suspected to be related in some way to the sphingosine 1-phosphate (S1 P) receptors. S1 P is a bioactive sphingolipid that mediates diverse cellular responses, such as proliferation, cytoskeletal organization and is involved in phenomena such as regulation of trafficking of immune cells, vascular homeostasis or cellular communication in the central nervous system. S 1 P is contained in body fluids and tissues at different concentrations, and excessive production of the pleiotropic mediator at inflammatory sites can participate in various pathological conditions. Studies of gene deletion and reverse pharmacology provide evidence that many effects of S1P are mediated via the five subtypes of S1P receptors coupled to G protein (S1P receptors). The S1 P1, S1 P2 and S1 P3 subtype receptors are widely expressed and represent the dominant receptors in the cardiovascular system. S 1 P1 is also a dominant receptor on lymphocytes and regulates its exit from secondary lymphatic organs. The S1P4 receptors are expressed in the lymphoid system and S1P5 in the white matter tract of the central nervous system (CNS).

The interactions of synthetic ligands with these S1P receptors offer novel strategies for broad therapeutic applications.

The S1P prototype receptor modulator, FTY720 (fingolimod, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol), targets four of the five S1P receptor subtypes and can act several levels to modulate lymphocyte trafficking via lymphocyte and endothelial S1P1 and, perhaps, other inflammatory processes through additional S1P receptor subtypes. FTY720 binds with high affinity to S1P1 (0.3 nM), S1P4 (0.6 nM) and S1P5 (0.3 nM) and with approximately 10 times lower affinity to S1P3 (3.1 nM), but not to S1P2. Ongoing clinical trials indicate that FTY720 can provide an effective treatment of relapsing-remitting multiple sclerosis (as described in, for example, "FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis" (FTY720 therapy exerts differential effects on subsets of T cells in multiple sclerosis "), Mehling M et al., Neurology, 2008 Oct 14; 71 (16): 1261-7).

There is also a need to prepare radiolabeled derivative of FTY720 that could be used to mimic the drug in order to further define the therapeutic action of FTY720, for example, to quantify its pharmacokinetics and organ distribution in patients.

Surprisingly, the inventors have identified derivatives of FTY720, which contain an atom which can be a radioactive isotope. Such derivatives are capable of mimicking the pharmacokinetics of FTY720 and physicochemical activities. For example, they can mimic one or more of the following properties of FTY720: organ distribution, affinity and selectivity for S 1 P receptors, phosphorylation kinetics.

BRIEF DESCRIPTION OF THE INVENTION In view of the properties of FTY720, there is a need to develop derivatives of FTY720 which can be used as tracers, or imaging agents, ie, which can mimic the properties of FTY720 despite the introduction of one or more radioisotopes. .

Iodine and bromine are particularly heavy atoms (with respective atomic weights of ca. 127 and 80 Da), especially compared to FTY720 (molecular weight of 307.5). Therefore, it is surprising that despite the introduction of such halogen atoms, which are expected to modify the physicochemical and pharmacokinetic properties of the compounds, it is possible to prepare FTY720 derivatives, which despite the introduction of the Halogen can bind to S 1 P receptors with an affinity profile and selectivity to FTY720, while maintaining similar pharmacokinetic properties. After radiolabelling, these compounds can be used for in vitro and in vivo imaging applications. When properly labeled with isotopes, these agents exhibit valuable properties as histopathological labeling agents, imaging agents and / or biomarkers for the selective labeling of S 1 P receptors, for example, for at least one of the S 1 P 1 subtypes , S1 P3, S 1 P4 and S 1 P5. More particularly, the compounds of the invention are useful as markers or radio-tracer for labeling S 1 P receptors in vitro or in vivo, in particular for labeling at least one of the subtypes of S1 P1, S1 P3 receptors. , S1 P4 and S 1 P5 in vitro or in vivo.

Additionally, these compounds tend to accumulate in myelin, possibly by a mechanism that is independent of their affinity for S1P receptors, such as insertion into myelin sheets. Hence they are also suitable for forming myelin images in diseases and disorders, where the myelin sheet has been altered, for example in demyelinating diseases.

Suitable radionuclides that can be incorporated into the compounds of the invention include: 231, 1241, 251, 131 I, 75 Br or 76 Br. The choice of the radionuclide to be incorporated in the compounds will depend on the specific analytical or pharmaceutical application. Thus, for in vitro labeling of S 1 P receptors and for competition assays, compounds incorporating 1 25 l or 13 l would be preferred. For diagnostic and investigative imaging agents (positron emission tomography (PET) or simple photon emission computed tomography (SPECT)). In a specific embodiment of the invention, the compounds that incorporate 1 2 l or 123l respectively are preferred.

These trackers can be used to image S1P receptors in tissue sections in vitro or in vivo, for example, to analyze the receptor occupancy of compounds having an affinity for S1P receptors, and thus evaluate the potential therapeutic application of such compounds.

Such trackers may also be used to diagnose or define the stage of diseases and disorders where the expression of S 1 P receptors is affected, for example, autoimmune or demyelinating diseases, such as multiple sclerosis. They can also be used to assess the populations of susceptible patients to benefit from treatment with a drug that acts through interaction with S1 P receptors, or to estimate the distribution of FTY720 in specific patient populations.

Compounds of the invention The present invention provides new derivatives of FTY720, in particular new radioactive derivatives of FTY720, ie, radiolabelled derivatives of FTY720, the use of radiolabeled derivatives of FTY720 as tracers for medical imaging in diagnostic and therapeutic applications.

As defined herein above, "derivatives of FTY720" refers to compounds having a structure identical or similar to FTY720 or FTY720-phosphate, and further containing at least one iodine or bromine atom, eg, at least one radioactive isotope of iodine or bromine.

FTY720 is 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol, as shown FTY720-phosphate refers to a phosphorylated form of FTY720, as shown The terms "radiolabeled derivatives of FTY720" and "radiolabelled compounds of the invention" refer to the derivatives of FTY720 as described herein, which are radioactive, ie, wherein at least one iodine or bromine atom is substituted with, for example, a corresponding radioactive isotope, that is, the radiolabelled compounds of the invention can contain at least one atom selected from 123l, 12 l, 125 | 131 () 75gr Q 76ß | G p0r example | 0 to \ minus one atom selected from 123, 0 124, The FTY720 derivatives and radiolabeled derivatives of FTY720 according to the invention are compounds of formula I where Xa is C ^ oalkyl or OCi-9alkyl, for example C8alkyl, for example, n-octyl; R, is H or CVealkyl or P03H2; and wherein at least one hydrogen atom, for example, at least one hydrogen atom bonded to a carbon atom, is replaced by an iodine or bromine atom.

In the radiolabelled derivatives of FTY720 of Formula I, at least one hydrogen atom, for example, at least one hydrogen atom linked to a carbon atom, is processed with, for example, replaced by, a radioactive isotope of iodine or bromine , for example, with an atom selected from 123l, 2l, 25l, 13l, 75Br or 76Br, for example with 1 23l or 124l.

In a specific embodiment, the radiolabelled derivatives of FTY720 of Formula I contain at least one atom selected from 123l, 12l, 25l, 131l, 75Br or 76Br, for example at least one atom selected from 123l and 12, for example containing 23l or 124l.

Preferably, the hydrogen atom which is substituted with, for example, replaced by a radioactive isotope is bonded to a radiolabelled carbon atom.

The iodine or bromine atom can be incorporated as a substituent on the aryl ring of the molecule, in which case the derivative is referred to as "aryl iodine derivative FTY720" or "aryl bromine derivative FTY720", Such aryl derivative FTY720 may contain one or more iodine or bromine atoms, for example, at least one radioactive isotope of iodine or bromine.

The present invention provides a compound, for example, a radiolabelled compound, of formula the where Rt is as defined above; at least one of A, and B, is I (iodine) or Br, being the other H; Y is C1-10alkyl or OC1-9alkyl, for example Xi is C8alkyl.

In a specific modality, R, is H or P03H2.

In another embodiment, X ^ is n-octyl or n-heptyloxy.

For example, R, is H and ^ is n-octyl, or F is P03H2 and Xi is n-octyl.

Still in another mode, either A- is selected from the group consisting of I (iodine) and Br and B, is H, or A, is H and is selected from the group consisting of I (iodine) and Br.

Preferably, R, is H or P03H2; at least one Ai and B, is I (iodine), being the other H; Y Xi is n-octyl or n-heptyloxy.

In the radiolabelled compounds of formula I, at least one iodine or bromine atom is substituted with, for example, replaced by, a radioactive isotope of iodine or bromine, for example, a radioactive isotope selected from 1231, 124l, 125l, 131l, 75Br or 76Br, for example selected from 125l or 2 l.

In another embodiment, the alkyl chain of the FTY720 derivative is terminated by a double bond, wherein at least one of the carbon atom is substituted with, for example, replaced by an iodine or bromine, the derivative is then referred to as " iodo allyl derivative FTY720"or" bromo allyl derivative FTY720".

The present invention further provides a compound, for example a radiolabelled compound, of formula Ib, where R2 is H, Ci-6alkyl, or P03H2; At least one of E, F and G is I (iodine) or Br, the others are H, for example at least one of F and G is selected from the group consisting of I (iodine) and Br, the others are H.

X2 is C1-8alkyl or OCi.7alkyl.

In another embodiment, X2 is 1, 6-n-pentylene or oxy-n-butyl.

In one embodiment, R2 is H or P03H2.

In another modality, either E, F or G is selected from the group consisting of I (iodine) and Br, the other being H; for example, E and G and F is selected from the group consisting of I (iodine) and Br.

Still in a further embodiment, R2 is P03H2, at least one of E, F and G is I (iodine) or bromine, the other H being. For example, R2 is PO3H2, E is H and either G is I (iodine) or bromine and F is H or, reciprocally, G is H and F is I (iodine) or bromine.

In another embodiment, E is selected from the group consisting of I (iodine) and bromine, and G and H are both H.

In the radiolabelled compounds of formula la, at least one iodine or bromine atom is substituted with, for example, replaced by, a radioactive isotope of iodine or bromine, for example, a radioactive isotope selected from 125 I, 124 I, 123 I, 131 I , 75Br or 76Br, for example selected from 125l and 12 l.

In the definitions of the compounds of formula I, Ia and I b as described herein, the terms iodo ("I") and bromine ("Br") refer, respectively, to iodine and bromine atoms, including all the isotopes of such atoms.

Accordingly, the compounds of formula I, la and I b, can be radiolabelled compounds, for example, the iodine atom can be selected from 1 251, 124 1, 123 1 and 1 31 1, and the bromine atom can be selected from 75Br or 76Br.

Preferably, the compounds of the invention contain at least one radiolabelled atom, for example, a selected atom of 123l and 124l.

When the compounds of formula I, la or I b have one or more asymmetric centers in the molecule, the present invention is to be understood as encompassing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof. Compounds of formula la or I b, when the carbon atom carrying the amino group is asymmetric, preferably have the S configuration on this carbon atom.

The compounds of formula I, la or Ib may exist in free or salt form. Examples of pharmaceutically acceptable salts of the compounds of formula I, la or Ib include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate salts, fumarate, maleate, benzoate, citrate, malate , methanesulfonate and benzenesulfonate, or when appropriate, salts with metals such as sodium, potassium, calcium and aluminum, salts with amines, such as triethylamine and salts with dibasic amino acids, such as the compounds and salts of the present invention encompass forms of hydrate and solvate.

Examples of compounds of formula la, for example, radiolabelled compounds of formula la, are Compound A 25 Compound H Examples of compounds of formula I b, for example, with radiolabelled formula la, are In the compounds exemplified above, the I atom can be substituted with, for example, replaced by, any of 231, 124l, 125l, 131l, 75Br or 76Br, for example 123l, 12 l, 125l or 131l, for example by 75Br or 76Br, or for example for 123l or 124l. In which cases the compounds are radiolabelled derivatives of FTY720.

Process The compounds of formula Ib, for example, compounds I to N are obtained according to Process 1, which is summarized as follows.

The processes are described in more detail later.

Step 1 A compound of formula (VI I) is obtained by reacting a compound of formula (V) with a compound of formula (VI) in the presence of suitable coupling reagents, for example, DIAD or DEAD and PPh3, in the presence of a solvent or a mixture of solvents, for example, dioxane, THF.

Step 2 A compound of formula I, J or N is obtained by reacting a compound of formula (VI I) in the presence of a suitable acid, for example, concentrated hydrochloric acid, concentrated sulfuric acid or trifluoroacetic acid, in the presence of a solvent, for example, dioxane, EtOH or MeOH.

Step 3 A compound of formula (VI II) is obtained by reacting a compound of formula (VII) with a phosphorylating agent, for example, a phosphorocloridate, diphenylchlorophosphate, cyanoethyl phosphate, a phosphoramidite, such as di-tertiarybutyldiethylphosphoramidite, in the presence of a solvent or a mixture of solvents, for example, DCM, THF or dioxane followed by an oxidative reaction with an oxidizing agent, for example H202.

Step 4 A compound of formula K, L or M is obtained by reacting a compound of formula (VI II) in the presence of a suitable acid, for example, concentrated hydrochloric acid, concentrated sulfuric acid or trifluoroacetic acid, in the presence of a solvent or a mixture of solvents, for example, dioxane, EtOH or MeOH.

Compounds of the formula la, for example, A, B, D, E, F and H are obtained according to Process 2, which is summarized by the following scheme.

Step 5 A compound of formula A, B or D is obtained by reacting a compound of formula (IX) in the presence of iodine, a suitable acid, for example, concentrated hydrochloric acid, concentrated sulfuric acid, trifluoroacetic acid, in the presence of a solvent or a mixture of solvents, for example, CH3CN, dioxane, EtOH or MeOH.

Step 6 A compound of formula (X) is obtained by reacting a compound of formula A, B or D in the presence of benzyl chloroformate, a suitable base, for example, sodium hydroxide in the presence of a solvent or a mixture of solvents , for example, CH3CN, dioxane, EtOH or MeOH.

Step 7 A compound of formula (XI) is obtained by reacting a compound of formula (X) with a phosphorylating agent, for example, a phosphorocloridate, diphenylchlorophosphate, cyanoethyl phosphate, a phosphoramidite, such as di-tertiarybutyldiethylphosphoramidite, in the presence of a solvent or a mixture of solvents, for example, DCM, THF or dioxane, followed by an oxidative reaction with an oxidizing agent, for example, H202.

Step 8 A compound of formula E, F or H is obtained by reacting a compound of formula (XI) in the presence of a suitable acid, for example, concentrated hydrochloric acid, concentrated sulfuric acid or trifluoroacetic acid, in the presence of a solvent or a mixture of solvents, for example, dioxane, EtOH or MeOH.

The present invention also provides a radiolabelled compound of formula (I 1 la) or (IVa).

The compounds of formula (I) and (IVa) are obtained by reacting the corresponding stannane, or borane in the presence of a radioactive alkali metal halide source.

The labeling of the compounds of formula (I lla) and (IVa) can be obtained by various techniques. For example, it can be carried out by reacting a trialkylstannane precursor, a borane precursor or a boronic precursor of the compound of formula (I 1a), (IVa) and an alkali metal halide, such as Na 1 23l, Na 2 1, Na125l, Na1 31 l, Na75Br or Na76Br in the presence of an oxidizing agent, such as chloramines-T, peracetic acid or aqueous solution of hydrogen peroxide, and an acid, such as hydrochloric acid, acetic acid or an acid buffer, of preference at room temperature and in a appropriate solvent. Labeling can also take place by exchange in an acid medium between the non-radioactive iodinated molecule and a radioactive alkali metal halide.

The radiolabelled compounds of the formula la, for example, compounds A, B and D can be obtained according to Process 3, which is summarized by the following scheme.

(XIV) Step 9 A compound of formula (XII) is obtained by reacting compound A in the presence of suitable protecting groups as described by Greene et al (Protective Groups in Organic Synthesis, Wiley), for example, alkyl t-butyl carbonate, acetonide, acetate ester, in the presence of a suitable base, for example, sodium hydroxide, in the presence of a suitable solvent or a mixture of solvents, for example, DMF, DIVISO, dioxane.

Step 10 A compound of formula (XIII) is obtained by reacting a compound of formula (XII) via a cross-coupling reaction of a suitable di-boron compound, for example, bis (pinacolato) diboro, bis (neopentyl) diboro in the presence of a suitable palladium catalyst, for example, PdCI2 (PPh3) 2-2PPh3, PdCI2 (dppf), in the presence of a suitable base, for example, K2C03, KOAc in the presence of a suitable solvent or a mixture of solvents, example, dioxane, DMSO and subsequently by hydrolysis in the presence of a suitable acid, for example, hydrochloric acid or potassium acid fluoride.

Step 11 A compound of formula (XIV) is obtained by reacting a compound of formula (XIII) in the presence of an iodine source, for example, Nal, in the presence of a suitable oxidizing agent, for example, chloramines-T, acid peracetic or aqueous solution of hydrogen peroxide, in the presence of a suitable base, in the presence of - a suitable solvent or a solvent mixture, for example, H20, THF, dioxane and subsequently by removal of the protecting group with a suitable acid , for example, hydrochloric acid, trifluoroacetic acid.

The radiolabelled compounds of formula Ib, for example, compounds I, J and N are obtained following a synthetic scheme analogous to Process 3.

Diseases As defined hereinbefore, "diseases or disorders where the expression of S1P receptors is affected" refer to diseases or disorders that result in an imbalance or dysfunction of one or more S1P receptors, for example, from any of the receivers of S 1 P1, S 1 P4, S 1 P5 and S 1 P3 For example, such diseases include inflammatory diseases, autoimmune diseases, demyelinating diseases, neurodegenerative diseases, brain diseases, cardiovascular diseases, atherosclerosis, cancer, or any disease wherein the expression of S1P receptor is affected.

As defined herein, autoimmune diseases include, but are not limited to, multiple sclerosis, systemic lupus erythematosus (SLE), arthritis, rheumatoid arthritis, diabetes, (e.g., diabetes mellitus type I, adult onset diabetes mellitus type). II), uveitis.

As defined herein, cardiovascular diseases include, but are not limited to, hypertension, heart rate dysregulation.

As defined herein, demyelinating disease includes, but is not limited to, multiple sclerosis, and disorders associated therewith, for example, optic neuritis and Guillain-Barré syndrome.

As defined herein, neurodegenerative diseases include, but are not limited to, progressive dementia, β-amyloid-related inflammatory diseases, Alzheimer's disease, amyloidosis, Lewy Body diseases, multi-infarct dementia, Pick's disease or atherosclerosis. cerebral.

The present invention is particularly suitable for patients affected or suffering from a disease selected from inflammatory diseases, autoimmune diseases, demyelinating diseases, neurodegenerative diseases, brain diseases, cardiovascular diseases, atherosclerosis and cancer, for example, from a disease selected from diseases inflammatory diseases, autoimmune diseases, demyelinating diseases, neurodegenerative diseases and brain diseases.

In another embodiment, the invention is directed to patients who are suspected of suffering from such a disease.

Uses in diagnosis and imaging As previously stated, the present invention provides novel derivatives of FTY720 as defined herein above, for example, iodinated or brominated FTY720 derivatives, for example, compounds of formula I, la or I b, which can be used as myelin sheet or S 1 P receptor tracer for in vitro and in vivo imaging applications using an appropriate imaging instrument, in particular for brain or spinal cord imaging.

There are several differences between PET / SPECT imaging and established MRI techniques, and both methods can be considered complementary. While MRI can be used to image lesions in, for example, multiple sclerosis, it has limitations that PET / SPECT scanners can overcome, for example, MRI methods are based on tissue water content and do not clearly differentiate hyperintensities of M RI T2-weighted that result from, for example, neurodegeneration following apoplexy, hemorrhage or inflammatory processes. In contrast, the compounds of the invention allow specific myelin imaging, either by following insertion into the myelin sheet or by binding to S1 P receptors expressed in myelin.

In addition, PE / SPECT imaging does not require the use of a Ge-based counter-enhancing agent, for example, to differentiate between chronic and acute (or active) lesions. Finally, MRI is counter-indicated in patients with metallic implants, cardiac pacemakers, cochlear implants, aneurysm insurance of older generation, implanted stimulators or metallic foreign bodies in the eye.

As defined herein before, "imaging instrument" refers to an instrument that can detect radiations emitted from radio-trackers administered to living subjects and can reconstruct the information obtained to provide flat and tomographic images. Such images may reveal the distribution and / or concentration of the radio-tracker as a function of time. Preferably, the "imaging instrument" of the present invention relates, but is not limited to, positron emission tomography (PET) or single photon emission computed tomography (SPECT).

These trackers can be used to image S1 P receptors in tissue sections in vitro or in vivo, in particular in the brain, for example, to analyze the receptor occupancy of compounds that have an affinity for S 1 receptors. P, for example, for the receivers of S 1 P 1, S 1 P 3, S 1 P 4 and / or S 1 P 5. The compounds of the invention are useful, for example, for determining the levels of inhibition of S 1 P receptors of a medicament acting on such receptors.

They can be used to evaluate the potential therapeutic application of such compounds. They can be useful to monitor the effectiveness of drug-therapies of such diseases.

These trackers can be used to diagnose the occurrence or examination of a disease or disorder related to S 1 P as defined herein, for example, autoimmune or demyelinating diseases, such as multiple sclerosis.

They can be used to evaluate if a patient is susceptible to being treated with a drug that acts through the interaction of S 1 P receptors, for example, to be treated with FTY720.

In a number of embodiments, the present invention provides 1.1 Derivatives of FTY720 as defined hereinbefore, for example, iodine or bromine derivatives of FTY720, for example, compounds of formula I, la or Ib, for example compounds of formula la and Ib; or corresponding radiolabelled derivatives thereof, for example, radiolabelled compounds of formula I, la or Ib, for example, compounds of formula la or Ib comprising at least one atom selected from 123l, 124l, 25l, 131l, 75Br or 76Br. Preferably, Compounds A to H, for example, Compounds A, C, E and / or G, or corresponding radiolabelled compounds. Preferably, the compounds selected from any of Compound A and Compound E and the corresponding radiolabelled compounds. 1.2 Derivatives of FTY720 as defined hereinabove, for example, compounds of formula I, la or Ib, for example, compounds of formula la or Ib; or the corresponding radiolabelled compounds, for example, radiolabelled compounds of formula I, la and Ib, for example, radiolabelled compounds of formula la or Ib, as labels for labeling S 1 P receptors, for example, to label at least one of receptors of S1 P1, S1 P3, S1 P4 and S1 P5, for example, to label S1 P1 and / or S1 P5 receptors. 1.3 Derivatives of FTY720 as defined hereinabove, for example, compounds of formula I, la or Ib, for example, compounds of formula la or Ib; and corresponding radiolabelled compounds, for example, radiolabelled compounds of formula I, la or Ib, for example, radiolabelled compounds of formula la or Ib, as markers for diseases or disorders where the expression of S1P receptor is altered, for example , a disease selected from an autoimmune disease, neurodegenerative disease, brain disease, or demyelinating disease, for example, multiple sclerosis. 2. The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, la or I b, by example, a radiolabelled compound of formula la or Ib, as radio-tracer, for example, for positron emission tomography (PET) or single photon emission computed tomography (SPECT). 2. 2 The use of a derivative of FTY720 as defined hereinbefore, for example an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, the or Ib, or the compounds corresponding radiolabels, for example, the radiolabelled compound of formula la or I b, for diagnosing diseases or disorders, wherein the expression of S1P receptor is altered, for example, a disease selected from an autoimmune disease, neurodegenerative disease, cerebral disease or demyelinating disease, for example, multiple sclerosis. 3. The use of a FTY720 derivative as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, or Ib, for example, a compound of formula la or I b; or the corresponding radiolabelled compounds, for example, the radiolabelled compound of formula la or Ib, for in vitro or in vivo imaging applications, for example, brain or spinal cord imaging, for example, with em mog raphy. positron ion (PET) or computed tomography scan of single photon emission (SPECT), for example, in a patient suffering from or suspected of having an autoimmune disease, neurodegenerative disease, brain disease or demyelinating disease, for example, multiple sclerosis. 4. 1 A method for diagnosing the onset of a disease or disorder, wherein the expression of S 1 P receptor is altered, for example an autoimmune disease or demyelinating disease, in a subject, wherein said method comprises using a radiolabel derivative of FTY720 as is defined hereinbefore, for example, and radiolabelled iodine or bromo derivative of FTY720 as defined hereinbefore, for example, a compound of formula la or Ib, as defined hereinbefore. 4. 2 A method for diagnosing a disease or disorder in a subject, wherein the expression of S 1 P receptor is altered using PET or SPECT, for example, to diagnose an inflammatory disease, autoimmune disease, neurodegenerative disease, brain disease or demyelinating disease, wherein said method comprises radiolabelling a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, la or I b, for example, a compound of formula lao I b, as defined hereinbefore. 4. 3 A method for diagnosing the appearance of a disease or disorder where the expression of the S 1 P receptor is altered, for example, an inflammatory disease, autoimmune disease, neurodegenerative disease, brain disease or innate desmiel disease, in a subject, wherein said method comprises a) administering a radio-typed derivative of FTY720 as defined hereinbefore, a radiolabelled iodine or bromine derivative of FTY720 as defined hereinbefore, eg, a radiolabelled compound of formula I, or Ib, by example, a compound of formula I, la or I b, as defined hereinabove, to the subject, and b) detect or measure the radiation emitted from the radiolabelled compound with an appropriate imaging instrument, for example, positron emission tomography (PET) or single photon emmission computed tomography (S PECT), and optionally c) reconstruct the information obtained in step b) to provide flat and tomographic images, which reveal the distribution and / or concentration of the radiolabelled compound as a function of time. 4. 4 A method for diagnosing the onset of a disease or disorder, wherein the S1P receptor expression is altered, for example, an autoimmune disease, neurodegenerative disease, brain disease or demyelinating disease, in a subject, as defined under 4.3 . above, including step a) a step a1) of preparing a radiolabeled derivative of FTY720 as defined hereinbefore, for example, by introducing an atom selected from the group consisting of 123l, 24l, 125l, 13l, 75Br or 76Br, into a derivative of FTY720.

Step a1) may consist of preparing a compound of formula I, or Ib containing an iodine or bromine atom, which is radioactive, for example, containing a selected atom of 123 l, 2 l, 125 l, 131 l, 75 Br or 76 Br, for example, selected from 123l or 12 l. 5. 1 A method for predicting whether a patient suffering from a disease or disorder selected from an inflammatory disease, autoimmune disease, demyelinating disease, and brain disease, will respond to a compound that acts as an S1P receptor modulator, eg, an agonist S1P receiver, for example, FTY720, comprising: a) administering a radiolabeled iodine derivative of FTY720 as defined hereinbefore, e.g., a compound radiolabelling of formula la and I b containing at least one radioactive iodine atom, to a patient, and b) detecting or measuring the radiation emitted from the radiolabelled compound with an appropriate imaging instrument, for example positron emission tomography (PET) or single photon emission computed tomography (SPECT). 5. 2 A method for predicting which patients will respond to compounds that act as an S 1 P receptor modulator, eg, an S1 P receptor agonist, eg, FTY720, as defined under point 5.1. above, which comprises step a) one step to 1) of preparing a radiolabeled derivative of FTY720 as defined hereinbefore, for example, by introducing an atom selected from the group consisting of 123l, 124l, 125l, 31l, 75Br or 76Br, for example, 23l or 12 l, in a derivative of FTY720 of the invention, for example, in a compound of formula I, la or I b. Step a) can consist of preparing a compound of formula I, la or I b, for example, of formula la or Ib, containing an iodine or bromine atom, which is radioactive, for example, containing at least one atom selected of 1 23l, 124l, 125l, 1 31 l, 75 Br or 76 Br, for example, containing at least one atom selected from 123l or 124l. 5. 3 A method for estimating the distribution of FTY720 in specific patient populations, for example, brain distribution, comprising a step of a) preparing a radiolabelled derivative of FTY720 as defined hereinbefore, for example, by introducing an atom selected from the group consisting of 123l, 12l, 125l, 131l, 75Br or 7eBr, for example 123l or 124l, in n derived from FTY720 of the invention, for example, in a compound of formula I, la or Ib; b) administering said radiolabelled compound to a patient population, for example, affected by a disease or disorder selected from an inflammatory disease, autoimmune disease, demyelinating disease and brain disease, or at risk of being affected by such disease, and c) visualize the distribution of FTY720 in the myelin or brain of such patients. The step of preparing a radiolabelled derivative may be to prepare a compound of formula I, or Ib, for example of formula la or Ib, containing an iodine or bromine atom, which is radioactive, for example, containing at least one atom selected from 123l, 12, 125l, 13l, 75Br or 76Br, for example containing at least one atom selected from 123l and 124l. 6. The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, Ib, or corresponding radiolabelled compounds thereof as defined hereinbefore, for example, a compound of formula I, or Ib containing at least one atom selected from 123l, 124 | 125 | 131 | 75gr Q 76gr pQr example containing at least one selected atom of 123l or 12 l, to monitor the effectiveness of a pharmacotherapy of a disease or disorder where the expression of the S1P receptor is altered, for example, an inflammatory disease, autoimmune disease, demyelinating disease, neurodegenerative disease or brain disease. 6. 2 The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720, for example, a compound of formula la or Ib, or the corresponding radiolabeling compound thereof, as defined hereinafter, for example, a compound of formula I, or Ib containing at least one atom selected from 123l, 12 l, 125 l, 31 l, 75 Br or 76 Br, for example, containing at least one atom selected from 1 23l or 12 l, as a tracer to form myelin images and / or visualize brain or spinal cord images in a subject, wherein said method comprises a) administering a radiolabelled derivative of FTY720 as defined hereinbefore, a radiolabelled iodine or bromine derivative of FTY720, eg, a radiolabelled compound of formula I, or Ib, as defined hereinbefore, to the subject , and b) detecting or measuring the radiation emitted from the radiolabelled compound with an appropriate imaging instrument, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT), and optionally c) reconstructing the information obtained in step b) to provide flat and tomographic images, which reveal the distribution and / or concentration of the radiolabelled compound as a function of time. 6. 3 Use as defined under point 6.2 above, comprising before step a) a step for preparing a radiolabelled derivative of FTY720, for example, by introducing an atom selected from the group consisting of 123l, 124l, 1ll, 131l, 75Br or 76Br, for example 1 3l or 1 24l, in a derivative of FTY720 of the invention. 6. The use as defined under item 6.2 above, comprising before step a) a step for preparing a compound of formula I, or Ib, for example, of formula la or I b, containing at least one atom selected from 123l, 125l, 24l, 131l, 75Br or 76Br, for example containing at least one atom selected from 1 23l or 2 l. 6. 5 Use as defined under point 6.2 or 6.4 above using a positron emission tomography (PET) or single photon emission computed tomography (SPECT). 6. 6 Use as defined under items 6.2 to 6.5 above in a patient suffering from, suspected of having, or at risk of suffering from an autoimmune disease, neurodegenerative disease, brain disease or demyelinating disease, e.g., multiple sclerosis . 6. The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, Ib, or corresponding radiolabelled compounds thereof, as defined hereinbefore, for diagnosing the onset of a disease or disorder where the expression of the S 1 P receptor is altered, for example, an autoimmune disease or demyelinating disease, e.g., multiple sclerosis . 6. 8 The use of a derivative of FTY720 as defined hereinbefore, for example an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, a or Ib, or compounds corresponding radio labels thereof, as defined hereinbefore, to diagnose the occurrence of a disease or disorder according to a method defined above under 4.3 or 4.4. 6. The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, Ib, or corresponding radiolabelled compounds thereof, to predict which patients will respond to compounds that act as an S 1 P receptor modulator, eg, to FTY720. 6. The use of a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula la or Ib, or radiolabeled compounds corresponding to it, to estimate the distribution of FTY720 in specific patient populations, for example, brain distribution. 7. A method for brain imaging or myelin imaging, comprising administering to a subject an effective amount of a radiolabelled iodine or bromine derivative of FTY720 as defined hereinbefore, eg, a radiolabelled compound of formula I, o Ib, for example, a radiolabelled compound of formula Ia or Ib. 8. A composition which comprises a compound of the invention, for example, a derivative of FTY720 as defined hereinbefore, for example, an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, la or Ib, or the corresponding radiolabelling compound thereof, and a pharmaceutically acceptable carrier or excipient. 9. The use of a radiolabelled compound of the invention, for example, a radiolabelled compound of formula I, la or I b, for example, a radiolabelled compound of formula la or Ib; or a combination as defined under 8; for labeling histopathological structures containing S 1 P receptors, for example, at least one of S1 P1, S1 P3, S1 P4 and S 1 P5 receptors, in vitro or in vivo.

For example, the use of a radiolabelled compound of formula I, la or Ib, for example, a compound selected from a radiolabelled Compound A to M, for example, a radiolabelled Compound A, C, E or G, is provided for performing a In vitro auto-radiography, and determine the distribution of S 1 P receptors in tissue section. Autoradiography can be done by quantitative whole-body autoradiography (QWBA).

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retarding agents and the like. The use of such media and agents for pharmaceutically active substance is well known in the art. The compound of the invention can be administered to a patient in an appropriate diluent or auxiliary, or in an appropriate carrier, such as human serum albumin or liposomes. The pharmaceutically acceptable diluent includes saline and aqueous buffer solutions. Auxiliaries may include resorcinols, non-ionic surfactants, such as polyoxyethylene oleyl ether and hexadecyl polyethylene ether.

In one embodiment of the invention, the compound of the invention, its enantiomer, stereoisomer, racemate or pharmaceutically acceptable salt, for example, the radiolabelled compound of the invention, is administered parenterally as injections (intravenous, intramuscular or subcutaneous). The compound, its enantiomer, stereoisomer, racemate or pharmaceutically acceptable salt, can be formulated as an aqueous, parenterally acceptable, pyrogen-free, sterile solution. The preparation of such parenterally acceptable solutions, duly taking into account the pH, isotonicity, stability and the like, is known to the person skilled in the art. Certain pharmaceutical compositions suitable for parenteral administration include a radiolabelled compound of the invention in combination with one or more sterile pharmaceutically acceptable powders, which can be reconstituted in sterile injectable solutions or dispersions just before use. The pharmaceutical compositions may also contain antioxidants, buffers, bacteriostats, solutes, which make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. A formulation for injection can contain, in addition to the radiolabelled compound of the invention, an isotonic vehicle, such as sodium chloride solution, Ringer's solution, dextrose solution, sodium chloride and dextrose solution, lactated Ringer's solution, dextran solution, sorbitol solution , a solution containing polyvinyl alcohol, or an osmotically balanced solution including a surfactant and a viscosity enhancing agent, or other vehicle as is known in the art. The formulations may also contain stabilizers, preservatives, buffers, antioxidants or other additives known to those skilled in the art.

An effective amount of a compound of the invention can be combined with a pharmaceutically acceptable carrier for use in imaging studies.

As defined herein, "an effective amount" refers to an amount sufficient to produce an acceptable image using a suitable method and available equipment, for example, PET or SPECT.

The effective amount can be administered in more than one administration.

The effective amount may vary according to factors such as the nature and severity of the condition being treated, the disease to be diagnosed or the state of the disease to be diagnosed, the nature of therapeutic treatments which the patient has experienced, the degree of susceptibility of the patient, his age, sex, weight and idiosyncratic responses of the patient as well as dosimetry.

The effective amount may vary depending on the instrument used and the factors related to the film. The choice of the effective amount and optimization of such factors are well known to the person skilled in the art. Finally, the doctor in charge will decide the amount of compound to administer to each individual patient and the duration of the imaging study.

For example, less than 1 microgram of the radiolabelled compound of the invention, for example, radiolabelled compound of formula I, or Ib, for example, a compound selected from radiolabelled Compounds A to M, for example Compound A to M radiolabelled, Example, Compound A, C, E or G radiolabelled, is administered, for example, for diagnostic or therapeutic purposes. Examples of effective amount of the radiolabelled compound of the invention to be administered in a method of the invention as defined herein, include about 1000 picograms to about 10 micrograms, eg, about 80 picograms to about 1.5 micrograms, for example , about 50 picograms to about 20 micrograms, for example, about 30 picograms to about 30 micrograms, for example, about 20 picograms to about 35 micrograms, for example, about 10 picograms to about 40 micrograms.

For example, the effective amount of the radiolabelled compound of the invention, for example, radiolabelled compound of formula I, or Ib, may be about 100 picograms, about 50 picograms, about 30 picograms, about 20 picograms, about 10 picograms, about 1. picogram, about 100 micrograms, about 80 micrograms, about 50 micrograms, about 40 micrograms, about 30 micrograms, about 20 micrograms, about 10 micrograms, about 5 micrograms, about 1 microgram.

In another embodiment, the radiolabelled compound of the invention, for example, radiolabelled compound of formula I, or Ib, can be administered as from about 0.1 to about 10 mCi, about 0.5 to about 80 mCi, about 1 to about 50 mC, approximately 1 to approximately 100 mCi.

Such ranges and amounts are particularly suitable when administering the radiolabelled compounds of the invention, for example, the radiolabelled compound of formula I, la or Ib, for example, a compound selected from radiolabelled compounds A to M, for example, Compound A, C, E or G radiolabelled, as labels, for example, imaging or diagnostic agents according to the method described hereinabove, or in a kit as described below.

In another aspect, a kit is provided, which includes a radiolabelled compound of the invention, its enantiomer, stereoisomer, racemate or pharmaceutically acceptable salt, as described above, in combination with a pharmaceutically acceptable solution containing a carrier such as serum albumin. human or an auxiliary molecule such as mannitol or glaciate. Human serum albumin for use in the kit can be made in any form, for example, through purification of the human serum protein or through the recombinant expression of a vector containing a gene encoding human serum albumin. Other substances can also be used as carriers, for example, detergents, diluted alcohols, hydrocarbons and the like.

In one embodiment, a kit can contain from 1 to about 50 mCi of a radiolabelled compound of the invention, its enantiomer, stereoisomer, racemate or pharmaceutically acceptable salt.

In a specific embodiment of the invention, a kit can contain the stereoisomer of unlabeled fatty acid, which has been combined covalently or non-covalently with a chelating agent, and an auxiliary molecule, such as mannitol, gluconate and the like. The unlabeled fatty acid stereoisomer / chelating agent can be provided in solution or in lyophilized form. The kit may also include other components that facilitate the practice of the described methods. For example, shock absorbers, syringes, film, instructions and the like can optionally be included as components of the description kits.

Therapeutic use The compounds of the invention can be used as a therapeutic agent to treat or prevent a disease or disorder where S1P receptor expression is altered as defined hereinbefore, for example, an autoimmune disease or demyelinating disease, for example, multiple sclerosis.

The terms "treatment" or "therapy" (especially of a disease or disorder where S1P receptor expression is altered) refer to prophylactic or preferably therapeutic treatment (including but not limited to, palliative, curative, symptom reliever). , reducing symptoms) of said diseases, especially the diseases mentioned above.

Additionally, it is provided: 1 0. A method for treating or preventing a disease or disorder where the expression of S 1 P receptor is altered, for example, an inflammatory disease, autoimmune disease, neurodegenerative disease, brain disease or demyelinating disease in a patient in need thereof , such method comprises administering an iodine or bromine derivative of FTY720 as defined hereinbefore, for example, a compound of formula I, Ia or Ib, or the corresponding radiolabeling compound thereof, as defined hereinbefore, or a pharmaceutically acceptable salt thereof.

The following non-limiting Examples illustrate the invention.

A list of used abbreviations is given below.

Boc tert-butyloxycarbonyl CH3CN acetonitrile DCC dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane DMF?,? '- dimethylformamide EtOAc ethyl acetate EtOH ethanol Et20 diethyl ether h hours HPLC high pressure liquid chromatography K2C03 potassium carbonate LC liquid chromatography eOH methanol min minutes my milliliter mmol millimole MS mass spectroscopy NaHCO3 sodium bicarbonate NaOH sodium hydroxide NH4OH ammonium hydroxide PG protective group Rt retention time (LC / MS) RT room temperature TFA trifluoroacetic acid THF tetrahydrofuran LCMS / HPLC conditions (% = percentage by volume) Method A (RtA = retention time A) Gison 331 pump coupled to a Gilson UV / VIS 1 52 detector and a Finnigan AQA spectrometer (ESI), a circuit injection valve of 50 μ? and a column Waters XTerra MS C 1 8 3.5 pm 4.6x50 mm, running a gradient of water + 0.05% TFA / Acetonitrile + 0.05% TFA from 95/5 to 1 0/90 over 8 min with a flux of 1.5 ml / min.

Method B (RtB = retention time B) Agilent 1 100 series; Waters column XBridge C1 8 2.5 pm; 3 x 30 mm; gradient: A water + 5% acetonitrile + 0.5 - 1.0% HC02H / B acetonitrile + 0.5 - 1.0% HC02H; 0 min 10B; 1.70 min 95B; 2.40 min: 95B; 2.45 min: 10B; flow 1.2 ml / min; column temperature 50 ° C.

Method C (Rtc = retention time C) Thar SFC 200, Chiralpak IC; 30 x 250 mm; Socratic: C02 / 2-propanol / 2-propylamine 75: 25: 0.25; flow 90 g / min; BPR: 150 bar (1 50x1 05 Pa) Method D (RtD = retention time D) UPLC-ZQ2000, Acquity column HSS-T3 1 .8 pm; 2.1 x 50 mm; gradient: A water + 5% acetonitrile + 0.5 - 1.0% HC02H / B acetonitrile + 0.5 - 1.0% HC02H; 0 min 2B, 4.3 min 98B; 5.0 min: 98B; 5.10 min: 2B; 6.0 min: 2B; 1 .0 ml / min flow Preparatory HPLC Gilson Trilution LC Column: SunFire C18, 30 x 1 0 mm, 5 um Levigante: Water (+0.1% TFA): acetonitrile (+ 0.1% TFA) from 85/1 5 to 63% 35 in 16 min; flow 50 ml / min. 1 H-NMR instruments: Bruker (360 MHz), Varian Mercury (400 MHz); Bruker Advance (600 MHz).

Example A: HCL salt of 2-amino-2-. { 2- (4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl.}. -propane-1,3-diol Step 1: (4- { 2- [4 - ((E) -6-iodo-hex-5-enMoxy) -fenM] -etM.} -2-metl-4,5-d hydroxalozol-4-yl) -methanol At 0 ° C, to a mixture of 4- [2- (4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl) -ethyl] -phenyl (260 mg, 1.1 mmol), (E) -6-iodo-hex-5-en-1 -ol (250 mg, 1.0 eq) and triphenylphosphine (290 mg, 1.0 eq) in THF (10 ml) is added DIAD (0.215 ml, 1.0 eq). The resulting mixture is stirred at RT for 1 8 hours and 24 hours at 50 ° C. 0.3 equivalent of DIAD and PPh3 are added and the mixture is stirred for an additional 72 hours at 50 ° C. 0.5 equivalent of DIADy PPh3 are added and the mixture is stirred for an additional hour at 50 ° C. The mixture is divided between AcOEt and saturated NH4CI. The organic phase is separated, dried over Sodium sulfate and concentrated in vacuo to give a crude beige oil (1.54 g). The crude product is purified by flash chromatography on silica gel using DCM / MeOH (100/0 to 90/1 0) as the solvent system. From the purification, (4- { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4,5-dihydro -oxazol-4-yl) -methanol is isolated as a colorless oil.

LC / MS: RtA 4.84 min, m / z: 444.0 [M + H] 1 H NMR (400 MHz, CDCl 3) d ppm 7.08 (d, 2H); 6.79 (D, 2H), 6.52 (m, 1 H); 6.01 (d, 2H), 5.30 (s, 1 H); 4.27 (m, 1 H); 4.09 (m, 1 H); 3.92 (t, 2H); 3.72 (m, 1 H), 3.45 (m, 1 H), 2.54 (m, 2H); 2.12 (m, 2H), 2.06 (s, 3H), 1.88 (m, 1 H), 1.75 (m, 3H), 1.57 (m, 2H).

Step 2: HCl salt of 2-amino-2-. { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1, 3-diol To a solution of (4- {2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazole -4-yl) -methanol (60 mg, 0.1 35 mmol) in EtOH (2 mL) is added concentrated hydrochloric acid (2.05 mL). The resulting mixture is stirred at 85 ° C for 2.5 hours. The solvents are removed in vacuo to give a beige paste. After precipitation in Et20, the HCI salt of 2-amino-2-. { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1,3-diol is isolated as a beige powder.

LC / MS: RtA 4.62 min, m / z: 419.9 [M + H] 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.80 (bs, 3H); 7.09 (d, 2H), 6.83 (d, 2H), 6.52 (m, 1 H), 6.22 (d, 2H), 5.37 (t, 1 H), 3.90 (t, 2H), 3.50 (m, 4H) 2.08 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H); 1.50 (m, 2H).

Example B: (R / S) mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((E) -6-iodo: hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid Step 3: (R / S) -ester of 4-. { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid At 0 ° C, to a solution of (4-. {2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4, 5-dihydro-oxazole-4-kil) -methanol (230 mg, 0.52 mmol) in DCM / THF (2 ml / 2 ml) is added 1 H-tetrazole (1 82 mg, 5.0 eq) and di-tert-butyldiethylphosphoramidite (0.433 mi, 3.0 eq). The resulting mixture is stirred RT for 6 hours. Then 30% by weight solution of H202 in water (0.1 59 ml, 10 eq) is added and the mixture is stirred for 1.5 hours at RT. The reaction mixture is quenched by the careful addition of a 1 N sodium thiosulfate solution (10 ml). The aqueous phase is extracted with DCM. The organic phases are combined, washed with brine, dried over sodium sulfate and concentrated vacuum to give a crude oil (500 mg). The crude oil is purified by flash chromatography on silica gel using DCM / MeOH (100/0 to 90/1 0) as the solvent system. From the purification, the (R / S) -ester of 4-. { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-Methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid (107 mg) is isolated as a clear oil with a purity of about 50% and is used as such for the next step.

LC / MS: RtA 5.53 min, m / z: 636.1 [M + H] Step 4: (R / S) - mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid To a solution of (R / S) -ester of 4-. { 2- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4, 5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid (107 mg, 0.168 mmol) in EtOH (2.5 mL) is added concentrated hydrochloric acid (2.54 mL). The resulting mixture is stirred at 85 ° C for 2.5 hours. The solvents are removed in vacuo to give a beige paste. After precipitation in Et20, the (R / S) mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((E) -6-iodo-hex-5-enyloxy) -phenyl] -butyl] phosphoric acid is isolated as a beige powder.

LC / MS: RtA 4.53 min, m / z: 500.0 [M + H] 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.09 (d, 2H); 6.82 (d, 2H); 6.52 (m, 1 H), 6.22 (d, 1 H); 3.89 (m, 4H); 3.53 (m, 2H); 2.08 (m, 2H); 1.78 (M, 2H); 1.65 (m, 2H), 1.49 (m, 2H).

Example C: TFA salt of 2-amino-2-. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1, 3-diol Step 1: (4- { 2- [4 - ((Z) -6-Iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4,5-dihydro-oxazole-4- il) -methanol Synthesis analogous to Example A step 1, starting with 4- [2- (4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl) -ethyl] -phenol (400 mg, 1.7 mmol) , (Z) -6-iodo-hex-5-en-1 -ol (250 mg, 1.0 eq). (4- { 2- [4 - ((Z) -6-Iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4,5-dihydro-oxazol-4-yl. ) -methanol (403 mg) is isolated as a clear oil.

LC / MS: RtA 4.76 min, m / z: 443.9 [M + H] Step 2: Salt of TFA of 2-amino-2-. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1, 3-diol Synthesis analogous to Example A step 2, starting with (4- {2- {4 - ((Z) -6-iodo-hex-5-enyloxy =) - phenyl] -ethyl} -2- methyl-4,5-dihydro-oxazol-4-yl) -methanol. After purification by reverse preparatory HPLC, 2-amino-2-TFA salt. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1,3-diol is obtained as a white powder.

LC / MS: RtA 4.42 min, m / z: 420.0 [M + H] 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.77 (bs, 3H); 7.08 (d, 2H); 6.84 (d, 2H); 6.40 (m, 1H), 6.29 (m, 1H), 5.40 (t, 1H); 3.92 (t, 2H), 3.50 (m, 4H), 2.13 (m, H), 1.72 (m, 4H), 1.53 (m, 2H).

Example D: (R / S) mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((z) -6-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid Step 3: (R / S) -ester of 4-. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid Synthesis analogous to Example B step 3, starting with (4-. {2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4 , 5-dihydro-oxazol-4-yl) -methanol. After the reaction work, (R / S) -ester of 4-. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid is used as such for the next step.

Step 4: (R / S) - mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid Synthesis analogous to Example B step 4, starting with (R / S) -ester 4-. { 2- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid. (R / S) - mono-ester. { 2-amino-2-hydroxymethyl-4- [4 - ((Z) -6-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid is isolated as a white powder.

LC / MS: RtA 4.44 min, m / z: 500.1 [M + H] 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.09 (d, 2H); 6.82 (d, 2H); 6.40 (m, 1 H); 6.30 (M, 1 H); 3.91 (m, 3H) 3.80 (m, 2H), 3.52 (m, 2H); 3.33 (bs, 2H); 2.52 (m, 2H); 2.12 (m, 2H); 1.72 (m, 4H); 1.54 (m, 2H).

Example E: HCl salt of 2-amino-2-. { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1, 3-diol Step 1: (4- { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4,5-dihydro-oxazol-4-yl) -metanol Synthesis analogous to Example A step 1 starting with 4- [2- (4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl) -ethyl] -phenol (505 mg, 2.15 mmol), 5- iodine-hex-5-en-1 -ol (728 mg, 1.5 eq). (4- { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl.} -2-methyl-4,5-dihydro-oxazol-4-yl) -methanol is isolated as a clear oil.

LC / MS: RtA 4.76 min, m / z: 444.0 [M + H] Step 2: Salt of HCI of 2-amino-2-. { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl} -propane-1, 3-diol Synthesis analogous to Example A step 2, starting with (4- {2- [4- (5-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro -oxazol-4-yl) -methanol (63 mg, 0.142 mmol). The reaction is carried out in dioxane at 50 ° C for 20 hours and then 70 ° C for 4 hours. The HCL salt of 2-amino-2-. { 2- [4- (5-iodo-hex-5-enyloxy) -phenyl] -etl} -propane-1,3-diol is obtained as a beige powder.

LC / MS: RtA 4.64 min, m / z: 420.0 [M + H] 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.77 (bs, 3H); 7.09 (d, 2H), 6.84 (d, 2H), 6.18 (s, 1 H); 5.60 (s, 1 H); 5.36 (t, 2H); 3.93 (t, 2H); 3.50 (m, 4H), 2.43 (m, 2H); 1 .75-1 .50 (m, 6H).

Example F: (R / S) mono-ester. { 2-amino-2-hydroxymethyl-4- [4- (5-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid Step 3: (PJS) -ester of 4-. { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4, 5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid Synthesis analogous to Example B step 3, starting with (4- {2- [4- (5-iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4,5-dihydro -oxazol-4-yl) -methanol. After purification by flash chromatography, the (R / S) -ester of 4. { 2- [4- (5-iodo-hex-3-eniloxt) -phenyl] -ethyl} -2-methyl-4,5-dihydro-oxazol-4-ylmethyl di-tert-butyl ester of phosphoric acid is used as such for the next step.

Step 4: (R / S) - mono-ester. { 2-amino-2-hydroxymethyl-4- [4- (5-iodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid Synthesis analogous to Example 2 step B, starting with 4-ester. { 2- [4- (5-Iodo-hex-5-enyloxy) -phenyl] -ethyl} -2-methyl-4, 5-dihydro-oxazol-4-ylmethyl. The reaction is carried out in dioxane at 50 ° C for 4 hours. After purification by reverse preparatory HPLC, the (R / S) mono-ester. { 2-amino-2-hydroxymethyl-4- [4- (5-hyodo-hex-5-enyloxy) -phenyl] -butyl} of phosphoric acid is isolated as a beige powder.

LC / MS: RtA 4.45 min, m / z: 499.9 [M + H] 1 H N R (400 MHz, DMSO-d 6) d ppm 7.09 (d, 2H); 6.84 (d, 2H); 6.19 (s, 1 H); 5.71 (s, 1 H); 3.95-3.82 (m, 4H), 3.55-3.20 (m, 6H); 2.43 (m, 2H); 1.8-1.5 (m, 6H).

Examples G and H: 2-amino-2- [2- (3-iodo-4-octylphenyl) ethyl] -1,3-propanediol and 2-amino-2- [2- (2-iodo-4-octylphenyl) ethyl] -1,3-propanediol To a solution of FTYH720 (3.2 g, 10.4 mmol) in 100 ml of wet methylene chloride, silver sulfate (3.25 g, 10.4 mmol) and iodine (2.64 g, 1 0.41 mmol) are added. Silver trifluoromethanesulfonate (0.1 3 g, 0.52 mmol) is added at room temperature and the resulting mixture is stirred for 18 hours at room temperature. The yellow solid silver iodide is filtered. The organic phase is washed with 15% aqueous NaHCO3, dried over sodium sulfate, filtered and evaporated to dryness.

The residue is purified on a column of silica gel to produce a mixture of iodine compounds 7 and 8 after drying. Purification by chromatography (column: Chiralpak IC, 30x250 mm, mobile phase: C02 / 2-propanol / 2- propylamine /5: 25: 25.25 (Socratic)) gave the title compounds as a white solid.

Example G: LC / MS: RtB 1.28 min, [M] + = 433.9 SFC RTC = 4.82 min 1 H NMR (500 MHz, DMSO-d 6) d ppm 7.62 (d, 1H); 7.01 - 7.20 (m, 2H); 4.43 (t, 2 H); 3.11 - 3.27 (m, 4H); 2.55 - 2.63 (m, 2H); 2.45-2.52 (m, 2 H); 1.38-1.57 (m, 4 H); 1.16-1.35 (M, 12 H); 0.76 - 0.93 (m, 3 H) Example H: LC / MS: RtB 1.29 min, [M] + = 433.9 SFC RTC = 5.58 min 1 H NMR (500 MHz, DMSO-d 6) d ppm 7.56 (d, 1 H); 7.06 - 7.21 (m, 2 H); 4.40 (t, 2 H); 3.17 - 3.27 (m, 4 H); 2.58-2.64 (m, 2 H); 2.41-2.47 (m, 2 H); 1.39-1.42 (m, 2 H); 1.20-1.31 (m, 12 H); 0.77 - 0.89 (m, 3 H) Example I: 2-amino-2- [2- [3-iodo-4- (heptyloxy) phenyl] ethyl] -1,3-propanediol In analogy to the procedure described for the synthesis of Example G, the title compound is prepared from 2-amino-2- [2- [4- (heptyloxy) phenyl] ethyl] -1,3-propanediol.

LC / MS: RtB 1.20 min, [M] + = 436.0 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.60 (s, 1H); 7.12 -7.18 (m, 1H) 6.8-6.78 (M, 1H); 4.42 (br s, 2H); 3.92 (m, 2H), 3.09-3.25 (m, 4H), 2.6-2.67 (M, 2H); 1.62-1.73 (m, 2H); 1.38-1.56 (m, 4H); 1.2-1.36 (m, 6H); 0.81-0.88 (m, 3H).

Example J: mono [(S) -2-2-amino-2-hydroxymethyl-3-iodo-4-octylphenyl) butyl] phosphoric acid ester a) 4-Hydroxymethyl-4- [2- (3-iodo-4-octylphenyl) ethyl] oxazolidin-2-one Benzyl chloroformate (0.37 ml, 2.47 mmol) is added to a suspension of the compound described in Example 7 (1 g, 2.3 mmol) in 2N NaOH (10 ml). The mixture is kept at room temperature overnight. Then, the mixture is acidified with 1 N HCl and extracted with methylene chloride. The organic phase is dried over filtered and concentrated Na 2 SO 4. The residue is purified on a column of silica gel to give the title compound as a white powder.

UPLCMS: RtD = 3.36 min; [M + H] + = 460 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.65 (s, 1 H); 7.59 (d, 1 H); 7.04 - 7.23 (m, 2 H); 5.08 (t, 1 H); 4.16 (d, 1 H); 4.06 (d, 1 H); 3.30 -3.41 (m, 2 H); 2.55 - 2.69 (M, 2 H); 2.42-2.47 (m, 2 H); 1.63 (dd, 2 H); 1 .47-1 .52 (m, 2 H); 1 .1 8-1 .25 (m, 10 H); 0.74 - 0.91 (m, 3 H) b) Monkey ester. { (R / S) -4- [2- (3-iodo-4-octylphenyl) ethyl] oxazolidin-2-one} of phosphoric acid To a solution of 4-hydroxymethyl-4- [2- (3-iodo-4-octylphenyl) ethyl] oxazolidin-2-one (815 mg, 1.77 mmol) in dichloromethane (5 mL) and THF (5 mL) at 0 ° C 1 H-tetrazole (621 mg, 8.87 mmol) and di-tert-butyl diethyl phosphoramidite (1.59 ml, 5.32 mmol) are added. After 18 hours at room temperature, the hydrogen peroxide (0.54 ml, 1 7.7 mmol) [30% in water] is added in the form of drops and then the mixture is stirred at room temperature for an additional 90 minutes. The reaction mixture is quenched with saturated Na2S203 and the water phase is extracted with dichloromethane. The organic layer is dried over Na 2 SO 4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel to give the compound as a yellow oil.

UPLCMS: RtD = 4.56 min, [M] + = 651 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.87 (s, 1 H); 7.67 (s, 1 H); 7.08 - 7.25 (m, 2 H); 4.06-4.21 (m, 2 H); 3.78 (d, 2 H), 1 .65-1.86 (m, 2 H); 1 .46-1.52 (m, 2 H) 1 .40 (s, 18 H); 1.17 - 1.34 (m, 14 H) 0.84 (t, 3 H). c) Separation of enantiomers of mono- ester. { (R / S) -4- [2- (3-iodo-4-octylphenylethyl] oxazolidin-2-one] phosphoric acid is carried out by HPLC on a Chiralpak AS-PREP column at the preparatory scale (heptane (iEtOH / MeOH 80 / 10/1 0 as mobile phase). d) Monkey ester. { (S) -2-amino-2-hydroxymethyl-4- [2- (3-iodo-4-octylphenyl) butyl]} of phosphoric acid To a solution of mono- ester. { (S) -4- [2- (3-iodo-4-octylphenyl) ethyl] oxazolidin-2-one} of phosphoric acid (30 mg, 0.046 mmol) in ethanol (0.5 ml) is added lithium hydroxide (0.5 ml, 2.09 mmol) solution at 10%. After 20 hours at 60 ° C, the reaction mixture is cooled to room temperature and stirred for 2 days. The concentrated HCl (0.5 ml) is added and the solution is stirred at room temperature for 1 hour. The mixture is neutralized with 4 N NaOH and concentrated. The residue is taken up in dichloromethane (2 ml), and fi ltered in Hyflo and the fi ltration cake is washed twice with dichloromethane. The solution is concentrated to give the title compound as a white powder.

LCMS: RtB 1.41 min; [M] + = 514 Example K: Monkey ester. { (S) -2-amino-2-hydroxymethyl-4- [2- (2-iodo-4-octylphenyl) butyl} ] of phosphoric acid In analogy to the procedure described for the synthesis of Example J, the title compound is prepared from 2-amino-2- [2- (2-iodo-4-octylphenyl) etl] -1,3-propanediol .

LCMS: RtB = 1.32 min; [M] + = 51 3.8 Example L: Monkey ester. { (S) -2-amino-2-hydroxymethyl-4- [2- (3-iodo-4- (heptyloxy) phenyl) butyl]} of phosphoric acid In analogy to the procedure described for the synthesis of Example J, the title compound is prepared from 2-amino-2- [2- [3-iodo-4- (heptyloxy) phenyl] ethyl] -1,3-propanediol .

LCMS RtB = 1.28 min; [M + H] + = 516.0 Example M: Preparation of aryl neopentyl boronate precursor Bis- (neopentl glicate) diboro a) [1, 1-Bis-hydroxymethyl-3- (2-iodo-4-octyl-phenyl) -propyl] -carbamic acid tert-butyl ester A mixture of 2-amino-2- [2- (2-iodo-4-octylphenyl) etl] -1,3-propanediol (1.01 mg, 0.25 mmol), (Boc) 20 (0.09 ml, 0.38 mmol) and 1 M NaOH (0.28 ml, 0.28 mmol) in dioxane (5 ml) is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate and the organic layer is dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel to give the title compound as a colorless oil.

LC / MS RtB = 1.99 min; [M] + = 533.8 1 H NMR (360 MHz, CDCl 3) d ppm 7.67 (s, 1 H); 7.07 - 7.1 5 (m, 2 H) 5.06 (s, 1 H) 3.90 (dd, 2 H); 3.67 (dd, 2 H), 3.42 (bs, 2 H), 2.63 -2.74 (m, 2 H); 2.49- 2.63 (m, 2 H), 1.81-1.96 (m, 2 H); 1 .56-1 .60 (m, 2 H); 1.49 (s, 9 H); 1 .30-1.43 (m, 10 H); 0.87 - 0.96 (m, 3 H) b) Ter-butyl ester of acid. { 5- [2- (2-Iodo-4-octyl-phenyl) -ethyl] -2,2-dimethyl- [1, 3] dioxan-5-yl} -carbamic To a solution of [1, 1-bis-hydroxymethyl-3- (2-iodo-4-octyl-phenyl) -propyl] -carbamic acid tert-butyl ester (230 mg, 0.43 mmol) in DMF (2). mi) is added 2,2-dimethoxy-propane (5.3 ml, 43.1 mmol), acetone (3.2 ml, 43.1 mmol) and pTsOH. H20 (8.2 mg, 0.043 mmol) at RT. Then, the reaction mixture is stirred for 1 hour. The solution is quenched with a saturated solution of NaHCO 3, extracted with ethyl acetate, then the organic layer is dried over Na 2 SO 4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel to give 240 mg of the title compound as a colorless oil.

LCMS RtB = 1.92 min; [M + H] + = 574.2 1 H NMR (360 MHz, CDCl 3) d ppm 7.55 (s, 1 H); 6.93 - 7.08 (m, 2 H), 4.90 (br.S., 1 H); 3.82 (d, 2 H), 3.60 (d, 2 H), 2.49 - 2.64 (m, 2 H), 2.30 - 2.47 (m, 2 H), 1.77 - 1.94 (m, 2 H), 1 .44 - 1 .46 (m, 2 H), 1 .37 -1 .423 (m, 9 H), 1 .36 (s, 3 H), 1 .34 (s, 3 H), 1. 16-1.30 (m, 10 H), 0.66 -0.92 (m, 3 H). c) Tert-butyl acid ester (2,2-dimethyl-5-. {2- [4-octyl-2- (4,4,5,5-tetramethyl- [1,2] dioxaborolan- 2-yl) -phenyl] -ethyl.} - [1, 3] dioxan-5-yl) -carbamic A 25 ml, 2-neck round bottom flask is loaded with PdCI2 (dppf) (14.2 mg, 0.017 mmol), KOAc (51.3 mg, 0.52 mmol) and bis- (neopentyl glycolate) diboro (43.3 mg, 0.1 9 mmol) and discharged with nitrogen. A solution of tert-butyl ester of acid. { 5- [2- (2-Iodo-4-octyl-phenyl) -ethyl] -2,2-dimethyl- [1, 3] dioxan-5-yl} Carbamic (1000 mg, 0.1 7 mmol) in DMSO (1 mL) is added and the solution is stirred for 3 h at 50 ° C. The product is extracted into ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The organic solvent is stirring under reduced pressure and the product is purified by flash chromatography on silica gel to give the title compound as a white solid.

LCMS RtB = 2.1 8 min; [M + H] + = 560.2 Example N: Preparation of pinacol boronate precursor: tert-butyl ester of (2,2-dimethyl-5-. {2- [4-octyl-2- (4,4,5,5-tetramethyl- [1, 3.2] dioxoborolan-2-yl) -phenyl] -ethyl.} - - [1, 3] dioxin-5-yl) -carbamic A 20 ml Supelco vial is loaded with 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride complex, dichloromethane (8.54 mg, 10.46 μm), potassium acetate (103 mg, 1. 046 mmol) and bis (pinacolato) diboro (97 mg, 0.38 mmol) and discharged with argon. A solution of tert-butyl ester of acid. { 5- [2- (2-Iodo-4-octyl-phenyl) -ethyl] -2,2-dimethyl- [1, 3] dioxan-5-yl} Carbamic acid (200 mg, 0.349 mmol) in DMSO (6 ml) is added and the solution is stirred for 4 hours at 80 ° C. The reaction mixture is quenched with HzO and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate, filtered, concentrated under reduced pressure and the crude product is purified by flash chromatography on silica gel to give the title compound as a white powder.

LCMS RtD = 1.90 min; [M + H] + = 574.4 1 H NMR (360 MHz, DMSO-d 6) d ppm 7.44-7.46 (m, 1 H) 7.21 (d, 1 H); 7.00 (d, 1 H); 6.51 (br.S., 1 H); 3.92 (d, 2 H); 3.69 (d, 2 H); 2.64 -2.72 (m, 2H) 2.52-2.56 (m, 2H); 1.78 - 1.85 (m, 2 H); 1.49- 1.58 (m, 2 H); 1 .41-1.46 (m, 9 H); 1 .34-1.36 (m, 6H) 1 .30-1.32 (m, 12 H); 1 .25-1.29 (m, 10H); 0.84 - 0.90 (m, 3 H).

Example O: Preparation of trifluoroboronate precursor: tert-butyl acid ester (2,2-dimethyl-5-. {2- [4-octyl-2- (trifluoroborolan-2-yl) -phenyl] -ethyl} - [1, 3] dioxan-5-yl) -carbamic To a solution of pinacolyl boronate (200 mg, 0.35 mmol) in methanol (2 mL) is added aqueous potassium acid fluoride (0.45 mL, 1.97 mmol). The resulting paste is stirred at RT for 15 min, concentrated in vacuo and then dissolved in hot acetone, filtered and concentrated in vacuo. The filtrate is recrystallized from hot methanol to give the title compound as a white solid.

LCMS RtD = 1.75 min; [M + K] + = 514.3 1 H NMR (360 MHz, DMSO-d 6) d ppm 7.16 (s, 1 H); 6.75 (s, 2 H), 6.39 (br.S., 1 H); 3.98 (d, 2H); 3.59 (d, 2H); 2.52-2.56 (m, 2 H); 2.39 -2.46 (m, 2H); 1 .75-1.82 (m, 2 H); 1 .48-1.56 (m, 2 H); 1.43 (s, 9H); 1 .31 - 1 .34 (m, 6 H); 1.223-1.30 (m, 10H); 0.82 - 0.92 (t, 3H).

Example P: General procedure for the preparation of product labeled with 123l via boronate precursors Na123l without added carrier (74 MBq in 0.1% aqueous NaOH) is placed in a 2 ml Wheaton vial containing the arylboronate precursor (100 ml of 4 10 2 M solution in 50% aqueous THF). It is sealed, covered with aluminum flake and the mixture is stirred for 5 min at room temperature.A drop of 10% aqueous sodium thiosulfate is added to decompose the excess of iodine. The 1 3l intermediate is deprotected in the presence of 3N HCl in ethyl acetate to give the desired compound 123l. The radioiodinated product is isolated by passing it through a Sep-pak cartridge of silica gel using pentane: EtOAc (50: 1) as a levigant.

GTPyS binding assay using S1 P receptor preparation / CHO membranes The test is based on the SPA technology (Amersham) and is run in a 96-cavity format. The membranes are prepared from CHO cells stably expressing the S 1 P receptor of interest. The aliquots are stored at -80 ° C. The membranes (5-10 g / well) resuspended in assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2 and 0.1% fat-free BSA) containing 25 g / ml Saponin and 10 μM. GDP are SPA beads coated with mixed WGA (final conc 1 mg / cavity). Ligand and [35S] GTPyS (1250 Ci / mmol, final concentration 0.2 nM) were added and the plate was sealed. After incubation at room temperature for 120 minutes under constant agitation, the plates are centrifuged for 10 minutes at 1 000xg to pelletize the SPA beads. Then the plates are measured on a TopCount NXT (Packard) instrument and the data is analyzed using the GraphPad PRISM computation program.

In particular, the EC50 values in nM for the following compounds at several S 1 P receptors are shown in the table below: Percentage of lymphocyte suppression in Lewis rats The property of returning home from lymphocytes can be measured in the following blood lymphocyte suppression assay: An S 1 P receptor agonist or vehicle is administered intravenously to rats. Tail blood for hematological monitoring is obtained on day 1 to give the individual baseline values, and at 2, 4, 8, 24 and 48 hours after the application. In this assay, the S 1 P receptor agonist suppresses peripheral blood lymphocytes, for example, by 50%, when administered at a dose of for example, < 20 mg / kg. Preferred S 1 P receptor agonists are additional compounds, which in addition to their S 1 P binding properties internalize / desensitize S 1 P receptors, thereby antagonizing inflammatory processes driven by lysophospholipids, including ie sphingosine 1 phosphate (S 1 P), sphinophosphorylcholine (SPC), lysophosphatidic acid (LPA), and others, on vasculature cells, for example, endothelial cells. The capacity for internalization / desensitization of compounds will be determined using CHO cells transfected with an S 1 P receptor labeled with human myc.

The radiolabeled FTY720 derivatives of the invention can be used, for example, to determine their distribution and concentration ex vivo in rats, or in vivo in non-human primates and humans, by using methods known to the skilled person, for example, as is described by Pauwels et al. (Current Pharmaceutical Design 2009, 1 5, 928-934) or Bergstroem et al (Eur J Nucí Med 1997, 24, 596-601).

Variations, modification and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and essential features of the present invention. Agree with this, the scope of the invention is to be defined not by the foregoing illustrative description and examples but instead by the following claims, and it is intended that all changes falling within the meaning and range of equivalence of the claims be encompassed in the same.

Claims (15)

1. REIVI NDICATIONS 1 . A compound which is selected from - a compound of formula I where Xa is Ci.10alkyl or OCi.galkyl, for example, C8alkyl; Ri is H or Ci-6alkyl or P03H2; and wherein at least one hydrogen atom is replaced by an iodine or bromine atom; - a compound of formula la, where the it is as defined before; at least one of A and Bi is I (iodine) or Br, the other being H; Y is CL Toalkyl or OCi-9alkyl, for example, is C8alkyl; - a compound of formula Ib Ib where R2 is H, d.ealkyl or P03H2; at least one of E, F and G is I (iodine) or Br, the others are H, for example at least one of, F and G are selected from the group consisting of I (iodine) and Br, the others are H , Y X2 is C1 -8alkyl or QC ^ alkyl. 2. The compound according to claim 1, wherein the compound is selected from - Compound A - Compound B - Compound C - Compound D - Compound Compuest Compuest Compuest 3. The compound according to claim 1, wherein the compound is selected from Compound I Compound J Compound K Compound L Compound M - Compound N 4. A compound according to any one of claims 1 to 3, comprising at least one atom selected from the group consisting of 123l, 25l, 124l, 1 31 l, 75 Br or 76 Br. 5. A compound according to any of claims 2 or 3, wherein the compound is selected from Compound A, C, E and G, and wherein the compound contains an iodine atom, which is 123l or 124l. A compound which is selected from - a compound of formula I 6. The use of the compound of any one of claims 1 to 5, as a diagnostic agent for a disease or disorder, in which the expression of S1P receptor is affected, for example, a disease or disorder selected from an inflammatory disease, autoimmune disease , demyelinating disease and brain disease. 7. The use according to claim 6, wherein the disease is multiple sclerosis. 8. The use of the compound of any one of claims 1 to 5 as an imaging agent for a disease or disorder, wherein the expression of S 1 P receptor is affected, for example, a disease or disorder selected from, for example. , as an agent of brain or spinal cord imaging. 9. The use of the compound of any of claims 2 to 5, as a tracer for a disease or disorder, wherein the expression of S 1 P receptor is affected, for example, a disease or disorder selected from an inflammatory disease, disease autoimmune disease, demyelinating disease and brain disease. 10. The use according to any of claims 6 to 9 using a technique selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), a tomographic imaging technique of nuclear medicine using gamma rays, for example, PET or SPECT. eleven . A method for diagnosing in a patient the appearance of a disease or disorder where the expression of the S 1 P receptor is altered, for example, a disease or disorder selected from an inflammatory disease, autoimmune disease, demyelinating disease and brain disease, in a subject, wherein said method comprises administering an effective amount of a compound of any of claims 2 to 5 to said patient. 12. A method for predicting whether a patient suffering from a disease or disorder selected from an inflammatory disease, autoimmune disease, demyelinating disease and brain disease, will respond to a compound that acts as an S1 P receptor modulator, eg, FTY720, in where said method comprises the steps of a) administering to the patient an effective amount of a compound of any of claims 2 to 5, and b) detect or measure the radiation emitted from the radiolabelled compound with an appropriate imaging instrument, for example, positron emission tomography (PET) or tomography computerized emission of simple photons (SPECT). 1 3. A method for monitoring the effectiveness in a patient of a pharmacotherapy of a disease or disorder, wherein the expression of the S1P receptor is altered, for example, a disease or disorder selected from an inflammatory disease, autoimmune disease, demyelinating disease , neurodegenerative disease or brain disease, wherein said method comprises the steps of a) administering to the patient an effective amount of a compound of any of claims 2 to 5, and b) detecting or measuring the radiation emitted from the radiolabelled compound with an appropriate imaging instrument, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT). 14. A method according to any of claims 1 to 13, wherein the compound is Compound A or Compound B, as defined in claim 2. 15. The use according to any of claims 6 to 10, wherein the compound is Compound A or Compound B, as defined in claim 2. SUMMARY New compounds of iodine or bromine are provided and their use as diagnostic agents and imaging agents for diseases or disorders where the expression of S 1 P receptor is altered.